Angiogenesis is likely to play a key role in the pathogenesis of inflammatory arthritis. Several angiogenic[unreadable] molecules, including vascular endothelial growth factor and angiopoietin 1, are increased during rheumatoid[unreadable] arthritis (RA), and inhibition of angiogenesis suppresses arthritis in animal models, such as collagen-induced[unreadable] arthritis (CIA). We recently identified a pro-angiogenic gene, angiopoietin-like 4 (Angptl4), as the seventh[unreadable] most highly over-expressed mRNA in arthritic paws of mice with CIA. Expression of human Angptl4 mRNA[unreadable] was also substantially increased in human arthritic synovium. Angiopoietin-like 4 (Angptl4) is structurally and[unreadable] functionally similar to the angiopoietins, in that it specifically inhibits apoptosis of vascular endothelial cells.[unreadable] Expression of Angptl4 as assessed in mice and humans is limited primarily to liver, kidney, adipose tissue[unreadable] and inflamed synovium. This limited tissue distribution suggests that Angptl4 may play a distinct angiogenic[unreadable] role in arthritic tissue. Specific targeting of angiogenic events occurring within arthritic synovium may be[unreadable] favorable therapeutically. Angptl4 binds endothelial cells and can induce tubule formation of endothelial cells[unreadable] in vitro. Since Angptl4 binds to and exerts specific effects on endothelial cells, it is highly likely that a[unreadable] receptor for Angptl4 on endothelial cells mediates these effects. Therefore, Angptl4 and its putative receptor[unreadable] represent a major, targetable axis in the treatment of inflammatory arthritis. In this proposal we will develop[unreadable] the key reagents needed to test the hypothesis that Angptl4 increases inflammatory processes by[unreadable] promoting angiogenesis in arthritic synovial tissues. We directly test this hypothesis by (1) determining the[unreadable] effects of Angptl4 depletion on arthritis in the CIA mouse model and by (2) identifying and characterizing the[unreadable] receptor(s) for Angptl4 on endothelial cells.